Technical field

The present invention relates to the field of organic synthesis and more specifically it concerns a process for the preparation of a compound of formula

as defined further below. The invention concerns also the compound (I) as well as its precursors and the process for manufacturing compound (I). Furthermore, it concerns also the use of compound (I) for the synthesis of β-santalol or of derivatives thereof.

Prior art

The compounds of formula (I) are novel compounds, and are useful starting materials for the preparation of β-santalol, and derivatives thereof, in a short and effective manner.

The β-santalol, and derivatives thereof, are well known perfuming ingredients, some of which of particular relevance. Therefore, there is always a need for alternative synthesis to produce them.

To the best of our knowledge, several processes have been reported in the literature for the preparation of β-santalol and derivatives thereof. One may cite the following references: US 419741 1, EP 10213 or WO 09/141781.

All of said processes use as key intermediate a compound of formula

In particular, US 4197411 and EP 10213 disclose the closest analogues of the present invention's compounds, indeed the compounds

are disclosed as key intermediates in the synthesis of β-santalol.

Alternatively, Herbert et al. in Tetrahedron Letters, 1970, 41 , report an alternative preparation of β-santalol involving a laborious sequence of double bond hydration/dehydration and bromination/debromination.

However, said approaches either require an expensive, or not easy to prepare industrially, starting material (e.g. Herbert et al.) or provide β-santalol with very low overall yields (e.g. US 419741 1 , EP 10213). None of said prior art documents suggests the present invention's embodiments.

Therefore, in the industry, there is still a need for a more efficient process for the preparation of β-santalol and derivatives thereof. The aim of the present invention is to solve said need by providing a process which allows the preparation of the targeted compounds with improved overall yields, as well as diminished number of synthetic steps.

Description of the invention

A first object of the present invention is a compound of formula

in the form of any one of its stereoisomers or mixtures thereof, and wherein the dotted line represents a carbon-carbon single or double bond, and R ^a represents a hydrogen atom or a Si(R ^b ) ₃ or (R ^b ) ₂ COH group, each R ^b representing C _1-6 alkyl group or a phenyl group.

Indeed, we have now found that β-santalol (an important perfuming ingredient), and derivatives thereof, can be advantageously prepared starting from a propargyl alcohol of formula (I) wherein R ^a is a hydrogen atom, or from the equivalent compound wherein the acetylene position is protected, wherein R ^a is not a hydrogen atom.

Said compound (I) can be obtained by various methods, as shown in the Examples. However we surprisingly found a process starting from the unknown intermediate (II) which allows higher yields. Therefore, a second object of the present invention concerns a process for the preparation of a compound (I), as defined above, comprising the following steps:

a) reacting a compound of formula

in the form of any one of its stereoisomers or mixtures thereof, and wherein the dotted line and R ^a have the same meaning as in formula (I), and X represents a halogen atom, a C acyl group, a C alkoxyl group, phenyl sulfonate optionally substituted by one or two C _1-3 alkyl groups such as tosylate, or a Ci _-4 alkyl sulfonate such as mesylate, or a group of formula OC(=0)OR°, wherein R ^c is a C ]-C ₇ alkyl group;

with a base having a pK _a above 16, preferably comprised between 16 and 30;

b) optionally, when R ^a is not a hydrogen atom, treating the compound obtained in step a) (methylene derivative resulting from the elimination of HX) with a suitable base or a fluorine salt to obtain compound (I) wherein R ^a is hydrogen atom.

According to any one of the embodiments of said aspect of the invention, said base of step a) is a C] _-6 alkaline alkoxide, such as sodium or potassium methoxide, ethoxide, iso-propoxide or ter-butoxide; a C ₂ . ₈ alkaline amide, such as LDA (lithium di- isopropyl amide); or a C _9- i ₂ polycyclic amidine or diamine, such as DBU. In particular, said base is a C3-6 alkaline alkoxilate such as sodium or potassium ter-butoxide, iso- propoxide or amyloxide.

The suitable bases or fluorine salt necessary for step b) are well known by a person skilled in the art. However one may cite, as non limiting examples, the following compounds: KOH, borax (Na ₂ B ₄ 0 ₇ ), KF or K ₂ C0 ₃ /18-C-6 ether.

The transformation of (II) into (I), in any of its embodiments and in particular for step a), is preferably carried out in the presence of solvent. Non-limiting examples of such a solvent are C _2- i2 amides, in particular C ₃ .g N-alkyl or Ν,Ν-dialkyl amide (e.g. acetamide, Ν,Ν-dimethyl-acetamide, N,N-dimethyl-form amide, N-acetyl piperidine or N-acetylpyrrolidine), C ₂ . ₆ sulphoxide (e.g. DMSO), Q.9 N-alkyl lactam e (e.g. N -methyl pyrrolidone) and mixtures thereof. More preferably, the solvent is DMF, DMSO, N- methyl pyrrolidone and mixtures thereof.

The temperature, at which the transformation of (II) into (I) according to the invention can be carried out, in any of its embodiments and in particular for step a), is comprised between -10°C and 100°C, preferably between 0°C and 80°C. Of course a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products and/or an eventual solvent.

The compound of formula (II), is also a novel compound and a further object of the present invention. Said compound (II) can be obtained according to a process comprising the following steps:

a') reacting a compound of formula

wherein the dotted line and X have the same meaning as indicated in formula (I); with a compound of formula R ^a -C=CY, wherein R ^a has the same meaning as in formula (I), and Y represents an alkaline metal or a MgZ or ZnZ group wherein Z is a halogen atom; b') optionally, when R ^a is not a hydrogen atom, treating the obtained compound (methylene derivative resulting from the elimination of HX) with a suitable base or a fluorine salt to obtain compound (I) wherein R ^a is a hydrogen atom.

The compounds responding to formula (III) are known compounds and can be prepared according to the literature, e.g. see US 419741 1.

Step b') can be performed as above described for step b).

The transformation of (III) into (II), in any of its embodiments and in particular for step a'), is preferably carried out in the presence of solvent. Non-limiting examples of such a solvent are C ₄ .g ethers or aromatic hydrocarbons and mixtures thereof. More preferably, the solvent is toluene or THF and mixtures thereof.

The temperature, at which the transformation of (III) into (II) according to the invention can be carried out, in any of its embodiments and in particular for step a'), is comprised between -20°C and 100°C, preferably between -10°C and 40°C. Of course a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products and/or an eventual solvent.

In particular, steps b) and b') are well known reaction and a person skilled in the art is able to apply its standard knowledge to perform them.

According to any one of the embodiments of said aspect of the invention. Z may represent a CI, Br or I atom.

According to any one of the embodiments of said aspect of the invention, Y may represent Li, Na, MgCl, MgBr or Mgl.

Examples of how to perform said processes are provided in the Examples part of the description.

As mentioned above, the propargyl alcohol (I) has been found to be a useful precursor of β-santalol; in particular compound (I) in which R ^a represents a hydrogen atom is a direct precursor of a key intermediate of β-santalol, and compounds (I) in which R ^a does not represent a hydrogen atom are direct precursors of compound (I) in which R ^a represent a hydrogen atom. Indeed propargyl (I), wherein R ^a is a hydrogen atom, can be used for the preparation of an aldehyde (IV), as defined below, which is known to be an important intermediate in the preparation of β-santalol and derivatives thereof. Consequently, a further object of the present invention is a process for the preparation of a compound of formula

in the form of any one of its stereoisomers or mixtures thereof, and wherein the dotted line has the same meaning as in formula (I); reacting a compound (I-a)

in the form of any one of its stereoisomers or mixtures thereof, wherein the dotted line has the same meaning as in formula (I);

with a complex selected amongst:

- a vanadyl derivative of formula [V ₂ 06SiPh ₂ ] _n or (PhaSiO^VO wherein Ph represents a phenyl group optionally substituted by one or two methyl groups, and n indicates that the compound is a monomeric, oligomeric or polymeric form;

- a Ru complex of formula [CpRuCl(PR3)], wherein Cp indicates a cyclopentadienyl optionally substituted by one to five Ci _-2 alkyl groups, and R represents Ci _-5 alkyl groups or a phenyl group optionally substituted by one or two methyl, methoxy or CF ₃ groups; or

- mixture of a cuprous halide, such as CuBr or CuCl, a Ti(OR) ₄ salt wherein R is as defined above, such as Ti(0 ¹ Pr) ₄ or (Ti(O ⁿ Bu)4, and a CMO carboxylic acid, such as p-toluic acid

optionally hydrogenating the compound of formula in the form of any one of its stereoisomers or mixtures thereof;

(obtained in step 1 if the dotted line of compound (I-a) represents a double bond) into a compound of formula

in the form of any one of its stereoisomers or mixtures thereof.

Step 1) is a Meyer-Schuster rearrangement and is a well known general reaction in the art. According to a particular embodiment, said complex of step 1) is:

- a vanadyl derivative of formula [V20 ₆ SiPh ₂ ] _n or (Ph3SiO) ₃ VO wherein Ph represents a phenyl group, and n indicates that the compound is a polymeric form (see L. A. heifits et al., Tetrahedron Letters 1976, 17, 2981 : H. Pauling et al. Helv. Chim. Acta 1976, 59, 1233; K. Takai et al. Tetrahedron Letters 1985, 26, 5585);

- a Ru complex of formula [CpRuCl(PMe ₃ )j, wherein Cp indicates a cyclopentadienyl (see T. Suzuki, M. Tokunaga, Y. Wakatsuki, Tetrahedron Letters 2002, 43, 7531); or

- mixture of a CuCl, (Ti(O ⁿ Bu) ₄ , and p-toluic acid (see R. K. Boeckman Jr et al. Helv.

Chim. Acta 2002, 85, 4532).

The transformation of (I-a) into (IV), in any of its embodiments and in particular for step 1 ), is preferably carried out in the presence of solvent. Non-limiting examples of such a solvent are water and C3.6 alcohols mixtures or aromatic hydrocarbons. More preferably, the solvent is a mixture of water and 'PrOH or toluene or xylene.

The temperature, at which the transformation of (I-a) into (IV) according to the invention can be carried out, in any of its embodiments and in particular for step 1), is comprised between about 80°C and about 160°C, preferably between about 100°C and about 150°C. Of course a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products and/or an eventual solvent.

Said complex in step 1) can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite salt concentrations ranging from 0.01 to 0.20 molar equivalents, relative to the molar amount of the starting compound (I-a) alcohol (I). Preferably, the complex concentration will be comprised between 0.03 and 0.10 molar equivalents. It goes without saying that the optimum concentration of the complex will depend on the nature of the latter and on the desired reaction time.

Step 2 can be performed using standard hydrogenation conditions, which are well known by a person skilled in the art. In particular it can be used a hydrogenation catalyst such as Ni(P2) (NaBH ₄ , Ni(OAc) ₂ , H ₂ , EtOH, W. Oppolzer, C. Chapuis, Tetrahedron Letters 1 83, 24, 4665) or Lindlar,(C. Fehr, I. Magpantay, J. Arpagaus, X. Marquet, M. Vuagnoux, Angew. Chem. Intl. Ed. 2009, 48, 7221).

The transformation of (IV) into (IV"), in any of its embodiments and in particular for step 2), is preferably carried out in the presence of solvent. Non-limiting examples of such a solvent are mixtures of a C alkyl alcohol, such as EtOH, and ¾0.

The temperature, at which the transformation of (IV) into (IV") can be performed, in any of its embodiments and in particular for step 2), is comprised between about 0°C and about 50°C, preferably between about 0°C and about 20°C. Of course a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products and/or an eventual solvent.

The H ₂ pressure, at which the transformation of (IV) into (IV") can be performed, in any of its embodiments and in particular for step 2), is comprised between about 1 bar and about 10 bars, preferably between about 1 bar and about 5 bars. Of course a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products and/or an eventual solvent.

Examples of how to perform said processes are provided in the Example part of the description.

According to any embodiment of the invention, and independently of the specific aspects, the compounds (I), (I-a), (II), (III) or (IV) can be in the form of any one of its stereoisomers or mixtures thereof. By the term stereoisomer it is intended any diastereomer, enantiomer, racemate or carbon-carbon isomer of configuration E or Z.

According to any one of the above embodiments of the invention, said compounds (I), (I-a), (II), (III) or (IV) are each in the form of a mixture of stereoisomers comprising more than 50% (w/w) of:

- the (1 RS,4SR) or the (1 RS,2SR,4SR) diastereoisomer, when the dotted line represents a single bond; or

- the (1RS,4SR) or the (1 RS,2RS,4SR) diastereoisomer, when the dotted line represents a double bond;

i.e. a compound having the relative configurations as shown in the formulae

and in a further embodiment said compounds consist essentially in the compound (I), (I-a), (II), (III) or (IV) each in the form of a mixture of stereoisomers comprising more than 70%, or 80% or 90%, (w/w) of the (1 RS,4SR), or of the (1 RS,2SR,4SR), or of the (1RS,2RS,4SR), diastereoisomer.

According to any one of the above embodiments of the invention, said compounds are each in the form of a mixture of stereoisomers comprising more than 50% (w/w) of:

- the (1 S,4R) or (1 S,2R,4R) enantiomer, when the dotted line represents a single bond; or

- the (1 R, 4S) or (1 R,2R,4S) enantiomer, when the dotted line represents a double bond; i.e. a compound having the absolute configuration as shown in the formulae

and in a further embodiment said compounds consist essentially in the compound (I), (I-a), (II), (III) or (IV) each in the form of a mixture of stereoisomers comprising more than 70%, or 80% or 90%, (w/w) of the above specified stereoisomer.

As typical examples of compounds (I), one may cite 1 -(( 1 RS,2SR,4SR)-2- methyl-3-methylenebicyclo[2.2.1 ]heptan-2-yl)prop-2-yn- 1 -ol, 1 -(( 1 S,2 J,4 ?)-2-methyl-3- methylenebicyclo[2.2.1]heptan-2-yl)prop-2-yn-l-ol, (li¾2i¾ ¾)-2-methy!-3- methylenebicyclo [2.2.1 ]hept-5-en-2-yl)prop-2-yn- l -ol or ( li?,2/?, S 2-methyl-3- methylenebicyclo[2.2.1 ] hept-5 -en-2-yl)prop-2-yn- 1 -ol

As typical examples of compounds (II), one may cite (lRS,2SR,3SR,4SR)-3- (chloromethyl)-2-methylbicyclo[2.2.1 ]heptan-2-yl)prop-2-yn- 1 -ol, (15,2i?,3i?,4i?)-3- (chloromethyl)-2-methylbicyclo[2.2.1 ]heptan-2-yl)prop-2-yn- 1 -ol, (1 RS,2SR,3SR,4SR)- 3-(bromomethyl)-2-methylbicyclo[2.2.1 ]heptan-2-yl)prop-2-yn- 1 -ol, (\S,2R,3R,4R)-3- (bromomethyl)-2-methylbicyclo[2.2.1 ]heptan-2-yl)prop-2-yn-l -ol, ([RS2RS,3RS,4SR)- 3-(chloromethyl)-2-methylbicyclo [2.2.1 ]hept-5-en-2-yl)prop-2-yn- l-ol, ( \R2R,3R,4S)- 3-(chloromethyl)-2-methylbicyclo [2.2.1 ]hept-5-en-2-yl)prop-2-yn- l-ol,

(l/?S,2/?^3/?S,4S/?)-3-(bromoomethyl)-2-methylbicyclo[2.2 .1 ]hept-5-en-2-yl)prop-2-yn- l-ol or (l^,2i?,3^,45 -3-(bromoomethyl)-2-methylbicyclo[2.2.1]hept-5-en-2-yl)prop- 2- yn-l-ol.

As typical examples of compounds (III), one may cite ( 1 RS,2SR,3SR,4SR)-3- chloro methyl-2-methylbicyclo[2.2.1 ]heptane-2-carbaldehyde, ( 1 S,2/?,37?,4/?)-3-chloro methyl-2-methylbicyclo[2.2.1]heptane-2-carbaldehyde, ( 1 RS,2SR,3SR,4SR)-3-bromo methyl-2-methylbicyclo[2.2.1 ] heptane-2-carbaldehyde, (LS',2 ?,3 ?,4/?)-3-bromo methyl- 2-methylbicyclo[2.2.1 ]heptane-2-carbaldehyde, (l ^S',2/?S,3/?S,4S ?)-3-(Chloromethyl)-2- methylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde, (li?,2i?,3i?,45)-3-(Chloromethyl)-2- methylbicyclo[2.2.1 ]hept-5-ene-2-carbaIdehyde, ( 1 RS,2RS,3RS,4SR)-3 -(bromomethy 1)- 2-methylbicyclo[2.2.1 ]hept-5-ene-2-carbaIdehyde or (li?,2i?,3i?,45)-3-(bromomethyl)-2- methylbicyclo [2.2.1 ] hept-5 -ene-2-carbaldehyde.

As typical examples of compounds (IV), one may cite (E or Z)-3- ((15 ^, ?,25i?,47?6 2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)acrylaldehyde, (E or Z)-3-((15',2S,4i?)-2-methyl-3-methylenebicyclo[2.2.1 Jheptan-2-yl)acrylaldehyde, (E or Z)-3-((1^5',25'i?,45'i?)-2-methyl-3-methylenebicyclo[2.2.1]h ept-5-en-2-yl)acrylaldehyde or (E or Z)-3-((li?,25',45)-2-metriyl-3-methylenebicyclo[2.2.1]hept-5 -en-2- yl)acrylaldehyde.

According to any one of the above embodiments of the invention, X may represent a halogen atom, such as a CI or Br atom or a sulfonate group as defined above. In particular said X may represent a CI or Br atom.

According to any one of the above embodiments of the invention, R ^a may represents a hydrogen atom or a Si(R ^b ) ₃ , each R ^b representing C alkyl group or a phenyl group. In particular, said R ^a represents a hydrogen atom.

For the sake of clarity, by the expression "wherein the dotted line represents a carbon-carbon single or double bond", or the similar, it is meant the normal meaning understood by a person skilled in the art, i.e. that the whole bonding (solid and dotted lines) between the carbon atoms connected by said dotted line, e.g. carbon 5 and 6, is a carbon-carbon single or double bond.

As mentioned above, the invention's compounds are useful intermediates for the preparation of important perfuming ingredient such as β-santalol.

Non-limiting examples of how to perform the preparation of β-santalol or a derivative thereof, from the compounds of formula (I) are provided in the Examples part of the description. However we can summarize such approach as follows :

i) preparing a compound (I), e.g. from compound (II) as described above;

ii) converting compound (I) in compound (IV) or (IV"), e.g. as described above;

iii) converting compound (IV") into β-santalol. Steps i) and ii) are described above. Step iii) can be performed as described in the literature, e.g. in US 419741 1, by Hoffmann et al, in J.Lieb.Ann.Chem, 1979, 743, or in WO 2009/141781. Practical examples of step iii) are provided in the Examples herein below.

However, as non-limiting example, one of the most direct manners to transform the aldehyde (IV") into β-santalol comprises the following reactions:

A. reducing (hydrogenation) the aldehyde (IV) or (IV") into and aldehyde of formula (V)

in the form of any one of its stereoisomers or mixtures thereof;

B. coupling said aldehyde ( V) with an aldehyde MeCH ₂ CHO (Aldol addition) to obtain an aldehyde (VI)

in the form of any one of its stereoisomers or mixtures thereof;

C. converting said com ound (VI) into the corresponding dienol derivative (VII)

in the form of any one of its stereoisomers or mixtures thereof, and wherein R' represents a C1-C3 acyl group or a C3-C8 silyl group;

D. reducing the enolate (VII) into a compound (VIII)

(VIII)

in the form of any one of its stereoisomers or mixtures thereof, and wherein R ⁴ has the same meaning as in formula (VI), and converting compound (VIII) into β-santalol.

According to a particular embodiment of the invention, said compounds (V) to (VIII) possess a configuration corresponding to the one described above for compounds (I) or (II).

Steps A) to D) can be performed according to standard methods well known by a person skilled in the art. For instance, the hydrogenation of step A) can be performed with Ni-Raney as catalyst.

For instance, one may cite the following method for each step:

step A) or B) according to EP 10213;

step C) according to Simmons et al. in Helv.Chim.Acta, 1988, 71, 1000, or WO 2005/037243; and

step D) according to Shibasaki et ah, in J.Org.Chem., 1988, 53, 1227 (where is reported the [1 ,4] hydrogenation of a dienol acetate derivative) or according to WO 08/120175.

Examples

The invention, in all its embodiments, will now be described in further detail by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (°C); the NMR spectral data were recorded in CDC1 ₃ with a 400 MHz or 125 MHz machine for ¹ II or ^l3 C respectively, the chemical shifts δ are indicated in ppm with respect to I MS as standard, the coupling constants J are expressed in Hz.

Starting compound (III) : (li?5,2i?5,3^»S,4Si?)-3-(Chioromethyl)-2- methylbicyclo[2.2.1 ]hept-5-ene-2-carbaldehyde (X = CI) 12a and (1^,2/?5',3/?5',45 ?)-3- (acetatemethyl)-2-methylbicyclo[2.2.1]hept-5-ene-2-carbaldeh yde (X = OAc) 12c as well as (\RS2SR,1SRASR)-!>-c \oro methyl-2-methylbicyclo[2.2.1 ]heptane-2- carbaldehyde (X = CI) 13a and ((lRS2SR,3SR,4SR)-2-fonnyl-2- methylbicyclol 2.2.1 ]heptan-3-yl)methyl acetate (X = OAc) 13c. were obtained according to the literature (see US 419741 1 and M. Baumann, W. Hoffmann, Liebigs Ann. Chem. 1979, 743.).

Other compounds of formula (III) were obtained as follows (see Scheme 1): Scheme 1 ;

wherein the letter following the number (see below) has the meaning: a: X= CI; b: X= Br; c: X= OAc; d: X= OH; e: X= OTs; f: X= OMs; qAS.2.^-re. S«>3-reromome^

12b (X = Br). In a 250ml round bottomed 4 necked flask equipped with a mechanic stirrer, a digital thermometer and a water refrigerant under Argon, were added CH C1 ₂ (50 ml), the BF ₃ O Et ₂ 0 (0.478 ml, 1.94 mmol). Then a solution of cyclopentadiene (3.59 g, 54.3 mmol) and the bromo aldehyde lib (7.9 g, 38.8 mmol) in CH ₂ C1 ₂ (15 ml) was added drop wise in 45 min at -20°. The solution was stirred at -20° for 30 minutes. After entire consumption of the starting material, the brown solution was poured onto ice (300g) and extracted with Et ₂ 0. The organic layer was washed with a 10% solution of NaHC0 ₃ , then with brine, and the organic phase was dried over Na ₂ S0 ₄ , filtered and evaporated to afford 9.2g of a brown viscous oil. A bulb to bulb distillation afforded 12b as a 5:95 endo/exo mixture in 70% yield.

Ή-NMR: 9.61 (s, 1 H), 6.38-6.29 (m, 2H); 3.18 (dd, J = 6, 9, 111); 3.15 (brs, 1 H); 2.99

(m, 2H); 2.95 (brs, 1 H); 1.42 (tq, J = 2, 9, 211); 0.95 (s, 3H).

1 ³ C-NMR: 203.8 (d); 136.9 (d); 136.2 (d); 57.5 (s); 50.7 (d); 47.2 (d); 46.0 (/); 45.4 (d);

34.2 (0; 14.8 (q).

(( 1. RS2SR.3SRASR)~3-bmmo methyl-2-methylbicyclof 2.2.1 lheptane-2-carbaldehvde 13b (X - Br). A suspension of 10% Pd/C (300 mg) in AcOEt (250ml) and 12b (6.6g, 14.12 mmol) was hydro genated for 15.5 hours (535ml of ¾ consumed). The suspension was filtered over Celite, dried and concentrated to obtain 6.4g of a yellow oil. A bulb to bulb distillation 90 0.09 mbar gave 13b in 95% yield.

1H-NMR: .9.43 (s, 1 H); 3.38 (d, J = 2.5, 1H); 3.36 (s, HI); 2.73 (ddt, J = 2, 4, 9, 1 H);

2.51 (brs, 1 H); 2.35 (brd, J - 2, 1 H); 1.66-1 .60 (m, 1 H); 1 .51 -1.24 (m, 5H); 1 .05

(.v, 3H).

¹³ C-NMR: 203.4 (d); 53.7 (5); 44.2 ( ); 43.7 (d); 41.2 (</); 36.5 (0; 31.8 (f); 23.0 (0; 21.0

(0; 12.5 (q).

13d (X = OH). A 3 necked 50ml round bottomed flask equipped with a magnetic stirrer, water refrigerant, under N ₂ was charged with KOH (628 mg, 9.51 mmol) and H ₂ 0 (1.714 ml, 95 mmol), MeOH (1 5 ml) and the acetate 13c (500 mg, 2.38 mmol). The reaction mixture was heated to reflux until full conversion (1 5 minutes), then the reaction was cooled down and poured onto an ice cold 10% H ₂ S0 ₄ solution and extracted with Et ₂ 0. The organic layer was washed with saturated NaHCQ ₃ , brine, and dried over N ₂ S04, then filtered and concentrated to 338mg of a crude yellow oil. A bulb to bulb distillation (13072 mbar) afforded pure 13d in 98% yield.

1H-NMR: 9.44 (s, Hi); 3.68-3.59 (m, 2H); 2.38 (brs, 1H); 2.29 (brs, 1H); 1.82 (brs, 1

OH); 1.66-1 .60 (m, 1 H); 1 .50-1 .25 (m, 6H); 1 .05 (s, 3H).

¹³ C-NMR: 204.8 (d); 60.6 (t); 52.9 (s); 43.9 (d); 43.7 (d); 39.4 (d); 37.2 (f); 23.1 (t); 21.7

(0; 12.5 (q). fi:RS SR3SR,4SR)-3-fmethyltoluenesulfonate)-2-niethylbicvcte[2.2J1 heptaiie-2- carbaldehyde 13e (X = OTs . A 3 necked 50ml round bottomed flask equipped with a magnetic stirrer, water refrigerant, under N ₂ was charged with alcohol 13d (400 mg, 2.38 mmol) and pyridine ( 15 ml). The solution was then cooled to 0° and TsCl (453 mg, 2.38 mmol) was added portionwise. The reaction was stirred at 20° overnight until full conversion. The reaction mixture was then poured onto an ice cold 10% H ₂ S0 ₄ solution and extracted with Et ₂ 0, the organic layer was washed with saturated NaHC0 ₃ , brine, then dried over Na ₂ S0 ₄ , filtered and evaporated to afford 910mg of the crude product. Purification over a 25g Si0 ₂ cartridge with cyclohexane/AcOEt 85 : 15 afforded pure tosylate 13e in 53% yield. Ή-NMR: 9.37 (s, 1 H); 7.80 (d, J = 16, 2H); 7.37 (d, J = 16, 2H); 4.10-3.97 (m, 2H);

2.59 (dt, J = 4, 10, 1 H); 2.49 (s, 3H); 2.35 (bis, 1 H); 2.26 (brrf, J = 3, 111); 1.63-1 .52 (m, I II); 1.42 ( , 311); 1 .34-1.24 (m, 2H); 0.99 (.?, 3H).

1 ³ C-NMR: 203.0 (d); 144.8 (.?); 133.0 (5); 129.9 (2d); 127.9 (2d); 68.6 (t); 52.8 (s); 43.6

(if); 39.7 (d); 39.5 (<0; 36.8 (f); 22.8 (t); 21 .7 (ø); 21.6 (t); 12.6 (ø).

(l RS.2SRJSR.4SR)-3-(rnethvlmethvlsulfonate)-2-methvlbicvclo 2.2. riheptane-2- carbaldehyde 13f (X = OMs). A 3 necked 50ml round bottomed flask equipped with a magnetic stirrer, water refrigerant, under N ₂ was charged with alcohol 13d (500 mg, 2.97 mmol), CH ₂ C1 ₂ (15 ml), and Et ₃ N (451 mg, 4.46 mmol), the solution was then cooled to 0° and MeS0 ₂ Cl (392 mg, 3.42 mmol) was added dropwise. The reaction mixture was stirred at 0° for 30minutes - full conversion and then poured onto an ice cold 5% HQ solution, and extracted with Et ₂ 0. The organic layer was washed with H ₂ 0, saturated NaHC0 ₃ , brine and dried over Na ₂ S0 ₄ , then filtered and concentrated to afford 740mg of the crude product. Purification on a 25g Si0 ₂ cartridge with cyclohexane/AcOEt 85/1 5 afforded mesylate I3f in 40% yield.

1H-NMR: 9.42 (s, I H); 4.30-4.16 (m, 2H); 3.00 (s, 3H); 2.71 (dt, J = 3, 10, 1H); 2.42 (brs, 1 H); 2.30 (bid, J = 3, I H); 1.68- 1.64 (m, 1H); 1 .53- 1 .25 (m, 5H); 1.07 (s, 311).

1 ³ C-NMR: 203.0 (d); 68.0 (t); 53.0 (s); 43.7 (</); 39.7 (d); 39.6 (d); 37.6 (q); 36.9 (t); 22.8 (0; 21.8 (0; 12.7 (i/).

(1.g&2I&4S¾)-2-ineth¥l-3-methylenebicvcIof2.2.1 1hept-5-ene-2-carbaidehvde 2.

Obtained in 60% yield from 12b according to the DBU elimination procedure used for 3. 1H-NMR: 9.67 (s, 1 H); 6.28 (m. 111); 6.21 (m, 111); 5.17 (s, 1 H); 4.77 (s, 1 H); 3.28 (s,

I H); 3.04 (s, I H); 1 .73 (m, 111); 1.66 (m, I H); 1.10 (s, 3H).

1 ³ C-NMR: 203.1 (d); 152.9 (s); 137.7 (d); 135.4 (d); 106.8 (i); 58.3 (5); 51.5 (d); 48.7

(^; 47.9 (0; 21 .0 (q). (1 A .2.¾,4.St)-2-meth¥l-3-methylen.ebicvc,lor2.2.1 ]heptane-2-carbaldehvde 3. A 1 M soln. of NaBH ₄ (0.36 ml, 0.36 mmol) in EtOH was added to a suspension of Ni(OAc) ₂ (89 mg, 0.36 mmol) in EtOH ( 1.3 ml) under H ₂ . After 30 min, a soln. of 2 (424 mg, 2.86 mmol) in EtOH/H ₂ 0 9: 1 (1 ml) was added. The mixture was stirred at 20° under 1 atm of ¾, until absorption of 1.0 mol.-equiv. of H ₂ . Filtration, then concentration of the reaction mixture afforded pure 3 in 95% yield. Also obtained in 53% yield from 13b (X = Br) or 13e (X = OTs), or 73% yield from 13f (X = OMs) according to the following DBU elimination procedure: To a 3 necked 100ml round bottomed flask equipped with a magnetic stirrer, a thermometer and a water refrigerant under Ar, were added 13 (bromide, or tosylate or mesylate 1 .613 mmol), DMF ( 10 ml). Nal (242 mg, 1.613 mmol) and DBU (614 mg, 4.03 mmol). The mixture was stirred at 80° for 50 hrs. The reaction was cooled to 20° and poured onto 2% aq. HC1, then extracted with Et ₂ 0, after washing with brine, the organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to obtain an oil. A purification over a 12g Si0 ₂ cartridge with cyclohexane/AcOEt 95:5 afforded 3.

1H-NMR: 9.40 (s, 1 H); 5.05 (s, 1 H); 4.66 (s, I H); 2.77 (bvd, J - 4.7, 1H); 2.52 (brd J =

3.2, 1 H); 1.74 (m, 2H); 1.67 (m, 1 H); 1.54 (m, 1H); 1.35 (m, 2H); 1.17 (s, 3H). ¹³ C-NMR: 201 .9 (d); 156.7 (s); 104.5 (/); 57.9 (s); 45.8 (d); 42.7 (d); 37.6 (t); 29.8 (i);

22.9 (0; 18.2 (g).

Example 1

Preparation of a compound (Y):

Scheme 2 :

Compounds (II) with the dotted line representing a C-C:

( ( It&lglJ^.^l-S-fchloroinethvD- -methyl icvciori.l.11heptan-2-yl)prop-2-vn- 1 - ol 14a. A solution of chloraldehyde 13a (0.5g, 2.53 mmol) in THF (5 ml) was added dropwise at 0°C to a solution of ethynylmagnesium bromide in THF (0.5M, 10ml, 5 mmol). After the addition was completed (5 min), the solution was poured onto saturated NH C1, washed with brine, dried, and evaporated under vaccuo at <40°C to obtain 470 mg of an oil. Purification over a 12g Si0 ₂ cartridge with cyclohexane/AcOEt 95/5 furnished 14a in 68% yield.

1H-NMR: 4.20 (brd, J - 3.3, 1H); 3.66 (dd, J = 4.6, 10.6, 1 H); 3.54 {dd, J = 1 1.1 , 12.4,

M l); 2.49 (brs, 1H); 2.42 (d, J = 2.8, IH); 2.32 (brs, 1 H); 2.05 (brd, J = 5.7, 1 H); 1.79 (dt, J = 4.3, 12.1 , IH); 1.56 (m, 2H); 1.42 (m, 3H); 1.27 (m, IH); 0.95 (s, 3H).

¹³ C-NMR: 83.4 (s); 73.3 (d); 69.1 (d); 48.8 (d); 46.3 (s); 44.1 (d); 43.4 (0; 39.4 (d); 36.0

(0; 24.5 (0; 20.2 (0; 12.0 (g).

(iWS2SK3SRA$m-3-(bm ometlwi -2-Me^

ol 14b. Obtained in 66% yield from 13b as a 4: 1 mixture of stereoisomers according to the procedure used for 14a.

1H-NMR: isomer A 4.19 (s, HI); 3.55 (dd, J - 4.2, 10, I H); 3.42 (dd, J = 9.2, 1 1.7. I ll);

2.51 (brs, IH); 2.42 (d, J = 2.5, I H); 2.39 (brs, IH); 1.99 (brs, 1 OH); 1.86 (dt, J = 3.3, 1 1.7, 1 II); 1.56 (dt, J = 3.3, 1 1.7, 2H); 1 .43-1.25 (m, 4H); 0.95 (s, 3H); isomer B 4.24 (s, I H); 3.51 (dd, J = 4.3, 9.3, 111); 3.41 (dd, J = 9.9, 1 1.2, IH);

2.52 (brs, I H); 2.47, (d, J = 2.5, IH); 2.25 (brs, IH); 2.15 (dt, J - 4.3, 1 1.2, Hi); 2.00 (brs, 1 OH); 1.65-1.60 (m, 2H); 1.41 -1.35 (m, 3H); 1.29-1.25 (w,

211); 0.96 (s, 3H).

°C-NMR: isomer A 83.3 (.y); 73.2 (d); 69.1 (if); 48.8 (i ); 46.9 (s); 44.3 ( ); 40.2 (d);

35.9 (0; 32.6 (0; 24.4 (0; 20.0 (t); 12.0 (q).

isomer B 83.2 (.v); 74.3 (d); 70.3 (^); 49.6 (d); 47.1 (>ν); 45.7 (ii); 41.0 (d); 36.5 (0; 33.4 (0; 24.5 (0; 20.0 (0; 12.0 (q). Compounds (I) with the dotted line representing a C-C:

solution of alcohol 14a (21 .8 mmol) in DMSO (150 ml) was added portionwise t-BuO (4.9g, 43.7 mmol) at room temperature. After the addition was complete, an exothermal (T=39°) was observed and the reaction temperature was left to reach room temperature for about 30 minntes. The cold solution was then poured onto saturated NH ₄ Ci, washed with H ₂ 0, brine, extracted with Et ₂ 0. The organic phase was dried (Na ₂ S0 ₄ ), filtered and evaporated to afford 4 in 78% yield.

Ή-NMR: 4.91 (s, I H); 4.76 (s, 111); 4.29 (m, IH); 2.73 (brd, J = 3.5, 1 H); 2.45 (d, J =

1.8, I H); 2.33 (brd, J = 3.6, I H); 2.23 (d, J = 4.3, I H); 1.73 (m, 3H); 1.47 (m,

2H); 1.29 (m, I H); 1.22 (.y, 3H).

1 ³ C-NMR: 161.5 (s); 103.9 (t); 82.9 (s); 73.7 (d); 66.5 (d); 50.0 (s); 47.2 (d); 45.3 (d);

36.7 (0; 30.5 (0; 23.5 (0; 16.8 (g). Alternatively, 4 was also obtained in 60% yield from 14b using the DBU elimination described for 3.

Alternatively, 4 was also obtained in 52% yield from 3, using the ethynyl addition procedure described for 14a. Compounds (II) with the dotted line representing a C=C: l -ol 21a. Obtained in 79 % yield from 12a, according to the above ethynyl addition procedure used for 14a.

^! H-NMR: 6.29 (dd, J = 4, 7.8, I H); 6.24 (dd, J = 4, 7.8, I H); 4.34 (d, J = 3.5, I H); 3.53

(dd, J = 4, 7.8, IH); 3.12 (br.v, IH); 3.03 (dd, J = 7.8, 8.4, IH); 2.90 (brs, IK);

2.51 (d, J - 1.8, I H); 2.14 (brs, 10H); 2.07 (dt, J = 4, 7.8, IH); 1.59 d, J =

8.4, IH); 1.49 (d, J = 8.4, I H); 0.89 (s, 3H).

, ³ C-NMR: 138.9 (d); 134.7 (d); 83.7 (s); 74.0 (d); 69.5 (d); 50.4 (s); 49.4 (d); 49.0 (d);

46.9 (/); 45.5 (d); 45.2 (t); 13.3 (q).

l-ol 21b. Obtained in 91 % yield from 12b according to the ethynyl addition procedure used for 14a. 1H-NMR: 6.3 1 -6.24 (m, 2H); 4.33 (dd, J = 2.2, 6.0, 1 H); 3.45 (dd, J= 4.6, 10.3, 1H);

3.15 (bis, 1H); 2.97 (bis, 1 H); 2.92 (dd, J= 8.5, 12.4, I H); 2.52 (d, J= 2.5, I I I); 2.15 J = 5.2, 10.3, I H); 2.08 (d, J= 6.6, 1 H); 1 .60 (d, J = 6.6, 1 H); 1 .47 (d, J = 6.6, IH); 0.89 (s, 3H).

1 ³ C-NMR: 139.0 (*/); 134.6 (rf); 83.7 (,s); 74.1 (</); 69.5 (d); 51 .4 (s); 49.7 (< ; 49.1 (d);

46.3 (i ); 45.1 ( ; 36.2 (t); 13.3 (?).

Compounds (I) with the dotted line representing a C=C:

(( I &4gj¾ -2-meth¥l-3-inetlwlenebic¥clor2.2.11hept-5-en-2-vI)prop-2- yn- I-ol 22, One pot addition/elimination: A solution of chloraldehyde 12a (7.9 g, 27.8 mniol) in THF (50 ml) was added drop wise at 0°C over 30 minutes to a solution of ethynylmagnesium bromide in THF (0.5M, 86.8 ml, 43.4 mmol. After the addition was completed, the mixture was allowed to warm to 20°C over a period of 2.5 hours. The solution was cooled down again to 0°C, and DMSO (250 ml) was added drop wise (maintaining the temperature at 5°C) following by an addition of iBuO (1 1.24 g, 100.2 mmol). The reaction temperature was left to reach room temp, and stirred at 20°C for 3hours (brownish suspension). The suspension was poured onto saturated NH4CI, washed with ¾0, brine, extraction was done with Et ₂ 0, which was dried then over Na ₂ S0 ₄ , filtered and evaporated to obtain 8.6g of an oil. Purification through a 100 g Si0 ₂ cartridge with cyclohexane/AcQEt 95 :5 afforded 22 in 67% yield.

Simple elimination: To a solution of 21 a (4.6 g. 21.8 mmol) in DMSO ( 150 ml) was added portionwise t-BuOK (4.9g, 43.7 mmol) at room temperature. After the addition was complete, an exothermal (Ί -39.2 ⁰ ) was observed and the reaction temperature was left to reach room temperature for about 30 min. The cold solution was then poured onto saturated NH ₄ CI, washed with H ₂ 0, brine, extracted with Et ₂ 0. The organic phase was dried (Na ₂ S0 ₄ ), filtered and evaporated to afford 22 in 84% yield.

1H-NMR: 6.19 (t, J = 1.8, 2H); 5.08 (s, IK); 5.00 (s, IH); 4.43 (bvs, I H); 3.21 (brs, 111);

3.08 (bis, IH); 2.56 (d, J = 2A , I H); 2.06 (brs, I H); 1.88 (bid, J = 8.8, HI); 1.54 (bre?, J= 8.8, IH); 1.13 (s, 3H).

, ³ C-NMR: 155.2 (s); 136.8 (d); 136.8 (d); 106.3 (0; 83.8 (s); 74.8 (d); 68.8 (d); 52.5 (d);

49.8 (. ); 48.4 (d); 47.1 (0; 21.2 (q)- Alternatively, 22 was also obtained in 57% yield from 2 by addition of ethynylMgBr, according to the procedure used for 14a.

Alternatively, 22 was also obtained in 77% yield from 21b according to the DBU elimination used for 3.

To summarize, 4 can be obtained with the following yields from 13:

Route: 13→14→ 4:53 % (X = CI) or 40% (X = Br) (according to the invention)

Route: 13→ 3→ 4: 27% (X = Br)

To summarize 22 can be obtained with the following yields from 12:

Route: 12→ 21 -> 22: 66 % (X = CI) or 70% (X = Br) (according to the invention) Route: 12→ 2 -> 22: 34% (X = Br)

Other compounds:

Scheme 2a:

General procedure for addition of mono-protected: A solution of «BuLi (1.6M/hexane, 1.3 mol.-equiv. for ethynyltrimethyl silane (-78°C), or 2.5 mol.-equiv. for 2-methyl-but- 3-yn-2-ol (-78°C)) was added dropwise at low temperature to a 10% THF solution of the monoprotected acetylene (1.0 mol.-equiv.). After 20 minutes at low temperature, a 10% THF soln. of the corresponding aldehydes 2 or 3 (1.0 mol.-equiv.) was added dropwise and after 20 minutes the temperature was equilibrated to 20°C for 1.5 hours. After addition of a saturated aqueous solution of NH ₄ C1, the reaction mixture was extracted with Et ₂ 0, the orgorganic phase was dried (Na ₂ S0 ₄ ), concentrated and purified by CC/Si0 ₂ (cyclohexane/AcOEt 95:5) to afford a mixture of diastereoisomers for analysis. 1 -(( 1 RS.2RSASR)-2-met vl-3 -methvlenebicvclo [2.2.1 ]hept-5-en-2-vl)-3- (trimethvlsilvl)prop-2-vn- 1 -ol (22d) Obtained in 53% yield from 2 as a 3 : 1 mixture of diastereoisomers at the carbinolic centre.

Ή-NMR: 0.21 (s, 9H); 1. 1 1 (s, 3H); 1.54 (d, J = 10, 1H); 1 .81 (d, J = 10, 1 H); 2.02 (d, J

= 7, 10H); 2.88 (brs, 111); 3.21 (bo, 1H); 4.40 (d, J = 7, 1H); 4.87 (s, l H);

5.03 (s, 1 H); 6.16-6.24 (m, 2H).

1 ³ C-NMR: 156.7 (s); 136.6 (2d); 106.0 (/); 105.2 (s); 90.8 (s); 69.0 (d); 52.5 (if); 50.7 (cf);

50.6 (s); 47. l (t); 19.7 (g); -0.2 (3g). 4-roetfayt- 1 -((lI&2&¾,4,¾)-2-ni.etlwl-3-methylenebicyclor2.2.1 1heptan-2-vi¾pent-2-yne- 1 ,4-diol (4c) obtained in 47% yield from 3 as a 80:20 mixture of stereoisomer at the carbinolic centre.

Ή-NMR: 1.19 (s, 3H); 1 .19-1.31 (m, 2H); 1 .41 - 1 .50 (m, 1 H); 1 .54 (s, 6H); 1.67- 1 .78 (m,

3H); 2.27 (bri/, J = 4, l H); 2.33 (brs, 10H); 2.37 (br.y, 10H); 2.72 (brd, J = 4, 1H); 4.29 (.v, 1H); 4.75 (s, I H); 4.91 (.v, 1H).

¹³ C-NMR: 161 .7 (.y); 103.9 (/); 90.5 (s); 81.0 (.s'); 66.5 (d); 65.2 (,s); 50.2 (s); 47.2 (d);

45.4 (if); 36.7 (t); 31 .4 (2g); 30.5 (t); 23.5 (t); 16.9 ( ).

Compound 4 was obtained in 56% yiled by deprotecting the above compounds according to J. Org. Chem, 2010, 22, 4306.

Example 2

Preparation of a compound (IV)

Scheme 3

Compounds (IV) with the dotted line representing a C-C:

(E)-3-f(lSiU _t ¾JJ?»$)-2-me^ 5. A mixture of alcohol 4 (100 mg, 0.521 mmol), /?-Toluic acid (12.05 mg, 0.089 mmol), CuCl (1.03 mg, 10.4μηιο1), and Ti(0«Bu)4 (2.3 mg, 6.77 μιηοΐ), xylene (5 ml), was heated to 150°C for 1 hour. The cold mixture was poured onto H ₂ 0, washed with brine, extracted with ether and the solvents were evaporated, obtaining 1 OOmg of a yellow oil. Purification over a 12g Si0 ₂ cartridge with cyclohexane/AcOEt 98:2 afforded 5 in 60% yield.

Alternatively, a mixture of alcohol 4 (150 mg, 0.851 mmol), (7.5 mg, 0.024 mmol) in xylene (5 ml) was heated at 145°C for 28 hours. The cold mixture was filtered through Celite, and the solvent was evaporated, the crude product (125mg, 58:42 E/Z) was purified over a 12g Si0 ₂ cartridge with cyclohexane/AcOEt 98:2 to afford 5 in 43% yield.

Alternatively 5 was also obtained in 69% isolated yield by hydrogenation of 23 ( 1.0-mol- equiv. of H ₂ ) over Raney-Ήχ (5% by weight) at 0° in EtOH/H ₂ 0 95:5.(93% based on recovered SM).

For analyses of 5, see C. Fehr et al. to Firmenich SA WO2009/141781 (2009/1 1 /26).

Compounds (IV) with the dotted line representing a C=C:

(Ι ι£ίΙ 2¾ ΧίΒ^

23. A mixture of propargylic alcohol 22 (1000 mg, 5.74 mmol) and CpRuCl(PMe ₃ )2 (123 mg, 0.344 mmol, T. Suzuki, M. Tokunaga, Y. Wakatsuki, Tetrahedron Letters 2002, 43, 7531 ) in PrOH ( 15 ml) and H ₂ 0 (4.5 ml) was heated at 100° for 72 hrs. The cold reaction mixture was evaporated under vacuum, diluted with pentane, dried (Na ₂ S0 ₄ ) and purified by CC/Si0 ₂ with cyclohexane/AcOEt 9: 1 to afford 23 in 60% yield, as a 95:5 E/Z mixture.

1H-NMR: 9.55 (d, J = 7.5, l H); 6.95 (d, J = 15.6, 111); 6.20 (dd, J = 7.5, 15.6, 1 H); 6.20

(m, 211); 5.14 (s. 111); 4.70 (s, 1 H); 3.27 (s, 1 H); 2.77 (.v, 1 H); 1 .68 (dt, J = 8.6,

1.6, 1 H); 1.62 (dr, J = 8.6, 1.6, l H); 1.16 (s, 3H).

1 ³ C-NMR: 194.4 (d); 165.7 (d); 155.6 (s); 136.9 (d); 135.3 (d); 130.7 (d); 106.4 (t); 52.0

(d); 5 1.9 (d); 50.1 (s); 48.0 (0; 25.6 (q).

Example 3

Preparation of a compound (V) and β-santalol Scheme 4 ;

3-((\SR 2RSARS)-2-methv\-3 -methvlenebicyclo [2.2.1] heptan-2- vDpropanal 6. Obtained in 85% yield by hydrogenation of 23 (2.0-mol-equiv. of ¾) over Raney-Ni ^' (5% by weight) at 0° in EtOH/H ₂ 0 95:5. (90% based on the recovered SM). For analyses, see H. Sonawane, R. Harikisan, N. S. Bellur, J. R. Ahuja, D. J. Kulkarni, J. Org. Chem. 1991 , 56, 1434; M. Saito, M. Kawamura, K. Ogasawara, Tetr. Lett. 1995, 36, 9003; D. Solas, J. Wolinsky, J. Org. Chem. 1983, 48, 1988; P. A. Christenson, B. J. Willis, J. Org. Chem. 1979, 44, 2012.

3-(Yl SR2RSAR$)-2-mzt\vt\-3 -methvlenebicyclo [2.2.1 lheptan-2-yl)propanal 6. Obtained in 85% yield from 5 by hydrogenation over 5% Pd/CaC0 ₃ (5%), MeOH/H ₂ 0 (96:4) according to C. Fehr, I. Magpantay, J. Arpagaus, X. Marquet, M. Vuagnoux, Angew. Chem. Intl. Ed. 2009, 48, 7221. For analyses, see H. Sonawane, R. Harikisan, N. S. Bellur, J. R. Ahuja, D. J. Kulkarni, J. Org. Chem. 1991, 56, 1434; M. Saito, M. Kawamura, K. Ogasawara, Tetr. Lett. 1995, 36, 9003; D. Solas, J. Wolinsky, J. Org. Chem. 1983, 48, 1988; P. A. Christenson, B. J. Willis, J. Org. Chem. 1979, 44, 2012.

Compound 6 is then converted into β-santalol following the same procedure described in WO 09/141781 by Fehr et al. (i.e compound of formula (V) → formula (VI) → formula (VII)→ β-santalol).

A comparison of the whole yields obtained with the invention's process and those obtained according to the closest prior art documents demonstrates the efficiency of the invention's process, see Scheme 5: Scheme 5 : Comparison of the yield using different process and starting from the same intermediate 12 and arriving at the same compound of formula (VI)

o a y e s:

Present invention: 33% (X=Cl) or 38% (X=Br)

EP10213 I J.lieb.Ann. Chem: <1 1 -15%

US 419741 1 : < 2% Example 4

Preparation of the optically active compounds (IV)

The asymmetric Diels- Alder reactions using dienophiles of type l la,b (see Scheme 6) may be performed using the methodologies described by Corey et al. from -95°C to -40°C: Org. Lett. 2010, 12, 1836; J. Am. Chem. Soc. 2007, J 29, 1498 (oxazaborolidines quaternized with AlBr ₃ ); Tetrahedron 2006, 62, 1 1397; J. Am. Chem. Soc. 2006, 128, 1346; J. Am. Chem. Soc. 2006, 128, 740; J. Am. Chem. Soc. 2004, 126, 13708; Org. Lett. 2003, 5, 3979; Org. Lett. 2003, 5, 2465; J. Am. Chem. Soc. 2002, 124, 9992 (oxazaborolidines protonated with TfOH or Tf ₂ NH); J. Am. Chem. Soc. 1996, 118, 5502. Scheme 6 : Diels- Alder reactions using dienophiles of type lla,b (e.e. of compound 12)

2a,b

X R T [°C] Catalyst yield exo/endo e.e.

11a CI H -78° 0.15 84 95:5 55

11a CI Me -78° 0.15 86 95:5 90

11a CI Me -78° 0.10 85 95:5 88

11a CI Me -78° 0.05 84 95:5 88

11a CI Me -78° 0.02 82 95:5 88

11a CI Me -95° 0.02 77 96:4 93

11a CI Me -40° 0.02 85 94:6 80

11 b Br Me -78° 0.02 73 94:6 81

Alternatively, the asymmetric Diels- Alder reactions using dienophiles of type lla,b may be performed using the methodologies of:

- Either T. Kaino, Y. Tanaka, K. Osawa, T. Yuri no, K. Maruoka, Chem. Commun.

2009, 1956, with BINAM derivatives at 0°C; or,

- K. Ishihara, H. Kurihara, M. Matsumoto, H. Yamamoto, J. Am. Chem. Soc. 1998,

120, 6920, with BINOL and borinic acid derivatives at -78°C (See also H. Yamamoto et al. J. Am. Chem. Soc. 1994, 116, 1561 ; J Org. Chem. 1989, 54, 1481 ; Tetrahedron Lett. 1989, 30, 7231), or

- Rawal et al. Tetrahedron Lett. 2007, 48, 1265; J. Am. Chem. Soc. 2002, 124, 5950;

Org. Lett. 2002, 4, 1 163; J Am. Chem. Soc. 2000, 122, 7843, using Jacobsen's chromium SALEN.

By applying the same experimental procedure as described above:

• (-)-(l S,2R,3R,4R)-13a was obtained from (-)-(l S,2R,3R,4R)-12a via hydrogenation with Pd/C with a yield of 87% ((-)-(lS,2R,3R,4R)-Ua: [a] _D ²⁰ = - 17.4, c - 3.50

CHCI3); (-)-(l S,2R,3R,4R)-14a was obtained from (-)-(l S,2R,3R,4R)-13a and ethynylmagnesium with a yield of 68% ((-)-( lS,2tf,3i?,4/?)- 14a: [a] _D ²⁰ = - 4.5, c = 1.7 CHCI3);

(-)-(l S,2R,4R)-4 was obtained from (-)-(l S,2R,3R,4R)-14a and tBuOK with a yield of 78% ((-)-( lS,2/?,4/?)-4: [a] _D ²⁰ = - 59.6, c = 0.90 CHCI3);

(-)-(l S,2S,4R)-5 was obtained from (-)-(lS,2R,4R)-4 and 5% (Ph2SiOVMe20) _n , (xylene, 140°) with a yield of 45% ((-)-(l S,2S,4R)-5: [a] _D ²⁰ = [a] _D ²⁰ = - 97.4, c = 0.40 CHCI3).